o:1699 Blocking STAT3/5 through direct or upstream kinase targeting in leukemic cutaneous T-cell lymphoma en Leukemic cutaneous T-cell lymphomas (L-CTCL) are lymphoproliferative disorders of skin-homing mature T-cells causing severe symptoms and high mortality through chronic inflammation, tissue destruction, and serious infections. Despite numerous genomic sequencing efforts, recurrent driver mutations have not been identified, but chromosomal losses and gains are frequent and dominant. We integrated genomic landscape analyses with innovative pharmacologic interference studies to identify key vulnerable nodes in L-CTCL. We detected copy number gains of loci containing the STAT3/5 oncogenes in 74% (n = 17/23) of L-CTCL, which correlated with the increased clonal T-cell count in the blood. Dual inhibition of STAT3/5 using small-molecule degraders and multi-kinase blockers abolished L-CTCL cell growth in vitro and ex vivo, whereby PAK kinase inhibition was specifically selective for L-CTCL patient cells carrying STAT3/5 gains. Importantly, the PAK inhibitor FRAx597 demonstrated encouraging anti-leukemic activity in vivo by inhibiting tumor growth and disease dissemination in intradermally xenografted mice. We conclude that STAT3/5 and PAK kinase interaction represents a new therapeutic node to be further explored in L-CTCL. lymphoma STAT3 STAT5 targeting T‐cell 1552099 10.15252/emmm.202115200 2023-06-09T13:33:27.265Z 44 yes 46 Helena Sorger University of Veterinary Medicine Vienna 0000-0002-3380-7770 Peter Wolf person 0000-0001-7777-9444 Lukas Kenner University of Veterinary Medicine Vienna person 0000-0003-0918-9463 Patrick T. Gunning person 0000-0003-0654-735X Ellen Heitzer person Marco Herling person Olaf Merkel person Roman Fleck person Heidi A Neubauer University of Veterinary Medicine Vienna person 0000-0001-7372-7786 Van Anh Nguyen person 0000-0003-2087-447X Fiona André person Jan P. Nicolay person Marion Wobser person Walter Berger person Anna Orlova University of Veterinary Medicine Vienna person 0000-0001-9262-7529 Martin L. Metzelder person Olasunkanmi O. Olaoye person Pimyupa Manaswiyoungkul person Ayah Abdeldayem person Gary Tin person Jana D Albrecht person Moritz Otte person Jennifer Ober person Lorenzo Cerroni person Regina Fink-Puches person Yi Pan person 0000-0001-6723-1370 Isabella Perchthaler person Thomas Graier person Michael Machtinger University of Veterinary Medicine Vienna person Marta Surbek University of Veterinary Medicine Vienna person Christine Pirker person Petra Kodajova University of Veterinary Medicine Vienna person 0000-0003-2746-7631 Gerald Timelthaler person Michaela Schlederer person Ines Garces de Los Fayos Alonso University of Veterinary Medicine Vienna person Till Braun person Isaac Lazzeri person Benjamin Spiegl person 0000-0003-4497-6120 Ricarda Graf person Abootaleb Sedighi person Elvin D de Araujo person 0000-0003-0716-2830 Andrea R Teufelberger person 0000-0002-1142-949X Daniel Pölöske University of Veterinary Medicine Vienna person Saptaswa Dey person 0000-0001-7532-7858 Pablo Augusto Vieyra-Garcia person 0000-0001-7101-9313 application/pdf 1310550 https://phaidra.vetmeduni.ac.at/o:1699 no yes 16 70 1552253 EMBO Molecular Medicine 11 14 12 Wiley 2022